EP0809653B1 - Helicobacter pylori antigen - Google Patents

Helicobacter pylori antigen Download PDF

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Publication number
EP0809653B1
EP0809653B1 EP96902390A EP96902390A EP0809653B1 EP 0809653 B1 EP0809653 B1 EP 0809653B1 EP 96902390 A EP96902390 A EP 96902390A EP 96902390 A EP96902390 A EP 96902390A EP 0809653 B1 EP0809653 B1 EP 0809653B1
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Prior art keywords
protein
pylori
composition
antigenic fragment
antigen
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EP96902390A
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English (en)
French (fr)
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EP0809653A1 (de
Inventor
Christopher John Smith
Robert Llewellyn University Of Newcastle Clancy
Allan Cripps
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Cortecs Ltd
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Provalis UK Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/205—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Campylobacter (G)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K2039/106—Vibrio; Campylobacter; Not used, see subgroups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to a novel antigen of Helicobacter pylori, or antigenic fragments thereof, the use of the antigen or fragments thereof in detecting Helictobacter pylori and kits comprising them, as well as vaccines comprising the antigen or fragments thereof and a method for isolation of the antigen.
  • This response often initially parallels an antibody response in serum although is generally characterised by the presence of IgA antibodies.
  • the immune response in secretion, including saliva rapidly diminishes following elimination of the antigen (eg bacteria or virus) from the body. Accordingly, the presence of antibody in mucous secretions reflects current, ie contemporary, infection.
  • secretious antibodies reflect the current status of colonisation of the microbe, such as in the gut, and thus is a useful monitor of contemporary infection.
  • Serum antibody persists for some time after the microbe is eliminated from the body.
  • a positive serum antibody test therefore, reflects both past and present exposure to antigen which is less helpful to the clinician.
  • a positive secretious antibody test indicates present or contemporary infection by the microbe.
  • H. pylori infection can be made by microscopy, microbiological culture or urease detection in gastric mucosal biopsies, urea breath test or by the presence of specific antibodies in serum ELISAs. It might be predicted that H. pylori infection, being an infection of the gastric mucosa, would elicit an IgA antibody response in gastric secretion. However, it has been discovered that H. pylori -specific antibody in mucous secretions is of the IgG class and not IgA as might have been expected. Little IgA antibody, if any, is detected. Accordingly, AU-A-9067676 is directed to the detection of IgG in mucous secretion specific to H. pylori antigen and thereby provides a means of monitoring current, ie contemporary, infection by that microorganism in mammals. The corresponding academic publication is Witt et al , Frontiers in Mucosal Immunology 1 693-696 (1991).
  • WO-A-9322682 discloses a convenient and reliable in vitro test for H. pylori. This test utilises an antigen preparation in a reaction with IgG antibody in a mucous secretion from a mammal being tested.
  • H. pylori novel antigens from H . pylori which can be used in diagnostic tests. These antigens should be specific, reliably purifiable, and should be characterised by good specificity and the lack of false positive results when used in such tests. In addition they may also form the basis of a vaccine useful either for the treatment or prophylaxis of H.pylori infection.
  • H. pylori Various proteins derived from H. pylori have been isolated and characterised and examples of such proteins include those disclosed in Evans et al, Infection and Immunity, 60(5), 2125-2127, (1992), EP-A-0329570 and Kostrzynska et al, J. Bacteriol., 173(3)., 937-946 (1991).
  • the present inventin relates to a novel antigenic protein derived from H. pyroli which can be used in diagnostic tests or from the basis of a vaccine.
  • the present invention provides a protein being an H. pylori antigen and having a molecular weight in the range 55-65 kDa, as determined under denaturing and reducing conditions.
  • the antigenic protein has, at its amino terminal end, the following amino acid sequence: or a sequence substantially homologous thereto.
  • a protein sequence may be regarded as substantially homologous to another protein sequence if a significant number of the constituent amino acids exhibit homology. At least 40%, 50%, 60%, 70%, 80%, 90%, 95% or even 99%, in increasing order of preference, of the amino acids may be homologous.
  • the present invention provides an antigenic fragment of the protein of the invention.
  • the antigenic fragment is a peptide having the sequence:
  • the antigenic protein, or fragments thereof, of the present invention can be provided alone, as a purified or isolated preparation, or as part of a mixture with other H. pylori antigenic proteins.
  • the invention provides an antigen composition comprising a protein of the invention and or one or more antigenic fragments thereof.
  • a composition can be used for the detection and/or diagnosis of H. pylori.
  • the composition comprises one or more additional H. pylori antigens.
  • the present invention provides a method of detecting and/or diagnosing H. pylori which comprises:
  • the protein, antigenic fragment thereof or antigen composition of the invention can be used to detect IgG antibodies.
  • the sample to be tested will be a biological sample, e.g. a sample of blood or saliva.
  • An example of a suitable method for detection of H.pylori using a sample of a mucous secretion is that described in WO-A-9322682.
  • the invention provides the use of an antigenic protein, antigenic fragment thereof or antigenic composition of the present invention in detecting and /or diagnosing H. pylori.
  • the detecting and/or diagnosing is carried out in vitro.
  • the present invention provides a method of isolating an antigenic protein of the invention, which process comprises the following steps:
  • the antigenic protein, antigenic fragment thereof or antigen composition of the invention can be provided as part of a kit for use in in vitro detection and/or diagnosis of H. pylori.
  • the present invention provides a kit for use in the detection and/or diagnosis of H. pylori comprising an antigenic protein, antigenic fragment thereof or antigen composition of the invention.
  • the antigenic protein or antigenic fragment thereof of the invention can be used to induce an immune response against H. pylori.
  • the present invention provides a composition capable of eliciting an immune response in a subject which comprises the protein or one or more antigenic fragments thereof of the invention.
  • the composition will be a vaccine composition, optionally comprising one or other suitable adjuvants.
  • a vaccine composition may be either a prophylactic or therapeutic vaccine composition.
  • the vaccine compositions of the invention can include one or more adjuvants.
  • adjuvants well known in the art include inorganic gels such as aluminium hydroxide or water-in-oil emulsions such as incomplete Freund's adjuvant.
  • Other useful adjuvants will be well known to the skilled man.
  • the present invention provides:
  • Rabbits were inoculated with the peptide MVTLINNE. Blood samples were assayed as described below to test for antibody response.
  • the assays were carried out using plates wherein each well is coated with 100 ⁇ l of 5 ⁇ g/ml H. pylori antigen (antigen preparation as described in WO-A-93/22682), followed by 300 ⁇ l of 1% Byco A solution as a post coat.
  • CDL wash buffer quantities for 1 dm 3 Tris 12.11 g 5M HCl 15 ml Distilled water 400 ml NaCl 87.66 g Thiomersal 0.1 g Tween 80 50 g
  • Peroxidase citrate buffer quantities for 1 dm 3 Distilled water 700 ml Citric acid 23.0 g NaOH 100 ml 30% H 2 O 2 0.5 ml Adjust pH to 4.0 with 1M NaOH.
  • the assay protocol was as follows:
  • the peptide elicits an anti- H . pylori antibody response.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Immunology (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Urology & Nephrology (AREA)
  • Biomedical Technology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Hematology (AREA)
  • Biotechnology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Virology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cell Biology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Food Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Claims (15)

  1. Protein, bei dem es sich um ein H. pylori-Antigen handelt und welches ein Molekulargewicht im Bereich von 55-65 kDa aufweist, wie unter Denaturier- und Reduzierbedingungen bestimmt wurde, und welches an seinem Aminoende die Sequenz:
    Figure 00170001
       oder eine dazu im wesentlichen homologe Sequenz aufweist.
  2. Antigenes Fragment eines Proteins nach Anspruch 1.
  3. Antigenes Fragment nach Anspruch 2, welches die Sequenz:
    Figure 00170002
       oder eine dazu im wesentlichen homologe Sequenz aufweist.
  4. Antigenzusammensetzung, umfassend ein in Anspruch 1 definiertes Protein oder zumindest ein antigenes in Anspruch 2 oder Anspruch 3 definiertes Fragment.
  5. Antigenzusammensetzung nach Anspruch 4, welche weiters ein oder mehrere andere H. pylori-Antigene umfaßt.
  6. Protein nach Anspruch 1, antigenes Fragment nach Anspruch 2 oder Anspruch 3 oder Antigenzusammensetzung nach Anspruch 4 oder Anspruch 5 zur Verwendung bei der Feststellung und/oder Diagnose von H. pylori.
  7. Verfahren zum Feststellen und/oder Diagnostizieren von H. pylori, welches umfaßt:
    (a) Inkontaktbringen eines in Anspruch 1 definierten Proteins, zumindest eines antigenen in Anspruch 2 oder Anspruch 3 definierten Fragments oder einer in Anspruch 4 oder Anspruch 5 definierten Antigenzusammensetzung, mit einer zu prüfenden Probe; und
    (b) Feststellen des Vorliegens von Antikörpern auf H. pylori.
  8. Verfahren nach Anspruch 7, wobei es sich bei der Probe um eine Speichelprobe handelt.
  9. Verwendung eines in Anspruch 1 definierten Proteins, zumindest eines antigenen in Anspruch 2 oder Anspruch 3 definierten Fragments oder einer in Anspruch 4 oder Anspruch 5 definierten Antigenzusammensetzung beim Feststellen und/oder Diagnostizieren von H. pylori.
  10. Verfahren nach Anspruch 7 oder Anspruch 8 oder Verwendung nach Anspruch 9, wobei das Feststellen und/oder Diagnostizieren in vitro erfolgt.
  11. Verfahren zum Isolieren eines Proteins nach Anspruch 1, welches umfaßt:
    (a) Anlegen von Kulturen von H. pylori, Züchten der Kulturen in geeigneten Bedingungen und Emten derselben, gefolgt von Waschen, um ein gewaschenes Zellpellet zu erhalten;
    (b) Resuspendieren der gewaschenen Zellen in einem geeigneten Puffer, gefolgt vom Zerschlagen der Zellen;
    (c) Zentrifugieren, um Zelltrümmer zu entfernen, Gewinnen des Überstandes, welcher lösliche Zellproteine enthält;
    (d) Unterziehen der erhaltenen Lösung einer Ionenaustauschchromatographie mit einer Gradientenelution und Analysieren der auf diese Weise erhaltenen Fraktionen auf die Gegenwart von Urease;
    (e) Vereinigen der ureasehaltigen Fraktionen und Unterziehen der vereinigten Fraktionen einer Gel-Permeationschromatographie;
    (f) Auswählen der geeigneten Spitze; und
    (g) Bestätigen der Gegenwart des spezifischen Proteins, welches ein Molekulargewicht im Bereich von 55-65 kDa im Isolat aufweist, und Isolieren des Proteins.
  12. Set zur Verwendung bei der Feststellung und/oder Diagnose von H. pylori, umfassend ein in Anspruch Idefiniertes Protein, zumindest ein antigenes in Anspruch 2 oder Anspruch 3 definiertes Fragment oder eine in Anspruch 4 oder Anspruch 5 definierte Antigenzusammensetzung.
  13. Zusammensetzung, welche in der Lage ist, eine Immunantwort in einem Subjekt hervorzurufen, und welche ein in Anspruch 1 definiertes Protein, zumindest ein antigenes in Anspruch 2 oder Anspruch 3 definiertes Fragment oder eine in Anspruch 4 oder Anspruch 5 definierte Antigenzusammensetzung umfaßt.
  14. Zusammensetzung nach Anspruch 13, welche eine Impfstoffzusammensetzung ist, die wahlweise weiters einen oder mehrere Hilfsstoffe umfaßt.
  15. Verwendung eines in Anspruch 1 definierten Proteins, zumindest eines antigenen in Anspruch 2 oder Anspruch 3 definierten Fragments oder einer in Anspruch 4 oder Anspruch 5 definierten Antigenzusammensetzung bei der Herstellung einer immunogenen Zusammensetzung, vorzugsweise eines Impfstoffes.
EP96902390A 1995-02-15 1996-02-15 Helicobacter pylori antigen Expired - Lifetime EP0809653B1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
GBGB9502899.9A GB9502899D0 (en) 1995-02-15 1995-02-15 Novel antigen
GB9502899 1995-02-15
PCT/GB1996/000351 WO1996025430A1 (en) 1995-02-15 1996-02-15 Helicobacter pylori antigen

Publications (2)

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EP0809653A1 EP0809653A1 (de) 1997-12-03
EP0809653B1 true EP0809653B1 (de) 2001-09-26

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EP (1) EP0809653B1 (de)
JP (1) JPH11503999A (de)
KR (1) KR19980701698A (de)
CN (1) CN1175955A (de)
AT (1) ATE206138T1 (de)
AU (1) AU714222B2 (de)
CA (1) CA2212952A1 (de)
DE (1) DE69615537T2 (de)
DK (1) DK0809653T3 (de)
ES (1) ES2164231T3 (de)
FI (1) FI973335A (de)
GB (1) GB9502899D0 (de)
IL (1) IL117151A (de)
NO (1) NO973753L (de)
NZ (1) NZ301334A (de)
PT (1) PT809653E (de)
WO (1) WO1996025430A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6599509B2 (en) * 1997-09-02 2003-07-29 Massachusetts Institute Of Technology Compositions and methods comprising helicobacter antigens for treatment and prevention of inflammatory bowel disease
CN1105185C (zh) * 1998-11-30 2003-04-09 上海晶莹生物技术有限公司 基因表达幽门螺杆菌细胞毒素相关基因a蛋白抗原制备工艺
AUPQ854100A0 (en) * 2000-07-03 2000-07-27 Helirad Pty Ltd Methods for monitoring treatment of helicobacter infection
SE0101030D0 (sv) * 2001-03-23 2001-03-23 Nordic Bio Ab Immunogenic cell surface proteins of helicobacter pylori

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5459041A (en) * 1988-02-18 1995-10-17 Enteric Research Laboratories, Inc. Campylobacter pylori antigens and uses thereof for detection of Campylobacter pylori infection
DE4139840B4 (de) * 1990-12-04 2005-06-02 Quidel Corp., San Diego Antigen-Zubereitung zum Nachweis von H. pylori
PL172125B1 (pl) * 1992-04-29 1997-08-29 Auspharm Int Ltd Sposób wykrywania trwajacych infekcji Helicobacter pyroli w komórkach ssaków PL PL PL

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KR19980701698A (ko) 1998-06-25
IL117151A0 (en) 1996-06-18
ATE206138T1 (de) 2001-10-15
NO973753D0 (no) 1997-08-14
NZ301334A (en) 1999-08-30
GB9502899D0 (en) 1995-04-05
AU4672896A (en) 1996-09-04
ES2164231T3 (es) 2002-02-16
WO1996025430A1 (en) 1996-08-22
IL117151A (en) 2001-06-14
DE69615537D1 (en) 2001-10-31
JPH11503999A (ja) 1999-04-06
FI973335A0 (fi) 1997-08-14
CA2212952A1 (en) 1996-08-22
CN1175955A (zh) 1998-03-11
NO973753L (no) 1997-08-14
AU714222B2 (en) 1999-12-23
EP0809653A1 (de) 1997-12-03
MX9706267A (es) 1997-11-29
DE69615537T2 (de) 2002-04-18
FI973335A (fi) 1997-08-14
PT809653E (pt) 2002-03-28
DK0809653T3 (da) 2001-11-19

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